This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In contrast to HIV-1 infection of humans and SIV infection of Rhesus macaques (RMs), which are associated with AIDS, natural SIVsmm infection of Sooty mangabeys (SM), is typically non-pathogenic. The mechanisms underlying this non-pathogenic phenotype remain largely unknown. Aim of this project is to understand the molecular and cellular basis for the differences in immune activation in SIV-infected SMs and RMs. To this end, we conducted an in vivo experiment in which naturally SIV-infected SMs are treated with a type I IFN agonist. The agonist is a fusion protein of the RM IFN-alpha2 with the IgG-Fc (rh-IFN-alpha2-Fc). This rh-IFN-alpha2-Fc molecule is bioactive and shows a longer in vivo half-life and higher solubility when compared to rhIFN-alpha2. In this study, eight naturally SIV-infected SMs were treated with 500,000 units of IFN-alpha2-Fc intravenously for twelve weeks. The key findings of this study are: (i) IFN-alpha2-Fc is bioactive in vivo in SMs and induces a strong ISG upregulation as detected by gene array analysis, thus indicating that SM cells are not intrinsically resistant to IFN stimulation;(ii) IFN-alpha2-Fc induces a 1-Log decline in SIV viral load that lasts for ~6 weeks;(iii) IFN-alpha2-Fc does not increase T cell activation, nor CD4+ decline in the treated animals throughout the study. Overall this experiment reveled that exogenous type I administration is not sufficient to induce disease progression in SIV-infected SMs. Further studies of manipulation of the type I IFN system in RMs and SMs are now being planned as part of this project.